| Autor: |
Heise CE; Department of Pharmacology, University of Virginia, Charlottesville, Virginia, USA., Santos WL, Schreihofer AM, Heasley BH, Mukhin YV, Macdonald TL, Lynch KR |
| Jazyk: |
angličtina |
| Zdroj: |
Molecular pharmacology [Mol Pharmacol] 2001 Dec; Vol. 60 (6), pp. 1173-80. |
| DOI: |
10.1124/mol.60.6.1173 |
| Abstrakt: |
The physiological implications of lysophosphatidic acid occupancy of individual receptors are largely unknown because selective agonists/antagonists are unavailable currently. The molecular cloning of three high-affinity lysophosphatidic acid receptors, LPA1, LPA2, and LPA3, provides a platform for developing receptor type-selective ligands. Starting with an N-acyl ethanolamide phosphate LPA analog, we made a series of substitutions at the second carbon to generate compounds with varying spatial, stereochemical, and electronic characteristics. Analysis of this series at each recombinant LPA receptor using a guanosine 5'-O-(3-[35S]thio)triphosphate (GTP[gamma35S]) binding assay revealed sharp differences in activity. Our results suggest that these receptors have one spatially restrictive binding pocket that interacts with the 2-substituted moieties and prefers small hydrophobic groups and hydrogen bonding functionalities. The agonist activity predicted by the GTP[gamma35S] binding assay was reflected in the activity of a subset of compounds in increasing arterial pressure in anesthetized rats. One compound with a bulky hydrophobic group (VPC12249) was a dual LPA1/LPA3 competitive antagonist. Several compounds that had smaller side chains were found to be LPA1-selective agonists. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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